A growing body of evidence indicates that decreased brain blood flow, increased reactive oxygen (ROS) and pro-inflammatory mechanisms accelerate the progression of neurodegenerative diseases such as Alzheimer?s Disease and Related Dementias (ADRD) including Vascular Contributions to Cognitive Impairment (VCID) (1), (3),(5),(6), (8). In older adults, inflammatory related diseases, such as cardiac disease or heart failure that lead to decreased brain perfusion and increased brain and systemic inflammation, are known to increase the risk for dementia and the development of ADRD and VCID (9),(10),(11),(12). ProNeurogen has been working with our University of Arizona collaborators to develop novel Angiotensin 1-7 (Ang-1?7) formulations to treat inflammation-related cognitive impairment in heart disease patients at for risk ADRD and VCID. These novel peptide formulations are designed to act on Mas receptors (MasR) within the brain vascular endothelium and neuronal cells to decrease brain ROS production, neuroinflammation and improve cerebral vascular blood flow. We have begun to translate these preclinical findings into novel peptide therapeutics to treat inflammation related cognitive impairment in patients with heart disease who are at risk for ADRD or VCID. We have an approved FDA IND # 125320 and support for Phase 2a trials for native Ang-(1-7) for treatment of cognitive impairment in heart failure (HF) patients and NIH support for our trial in cardiac bypass surgery patients (CABG). We are currently enrolling in these studies. Our current approved treatment protocol is once a day, subcutaneous 100 microg/kg injection using a standard needle and syringe for 85 days in our HF patients. However, in order to increase patient compliance and comfort with injections as well as accelerate commercialization we are currently investigating new formulations and injection methods that are more patient friendly and easier to administer. The goal of the present Phase I project is to begin development of a microneedle injection platform for the administration of our novel peptide therapies for treating brain inflammation related cognitive impairment. We will begin feasibility studies with the 3M Drug Delivery Systems to develop a microneedle injection platform for our Ang-(1-7) peptides. We will take advantage of 3M?s extensive experience in transdermal manufacturing expertise to complete the 2 principal objectives of this project: 1. Objective 1. Complete in vitro physiochemical analysis of loading and ejecting 10mg/ml Ang (1-7) peptides with the 3M Hollow Microstructured Transdermal System (hMTS). 2. Objective 2. Complete a PK study of Ang (1-7) peptides comparing 3M hMTS to subcutaneous injections in swine.